Exploring c‐Met kinase flexibility by sampling and clustering its conformational space
Identifieur interne : 000564 ( Istex/Corpus ); précédent : 000563; suivant : 000565Exploring c‐Met kinase flexibility by sampling and clustering its conformational space
Auteurs : Yasmine Asses ; Vishwesh Venkatraman ; Vincent Leroux ; David W. Ritchie ; Bernard MaigretSource :
- Proteins: Structure, Function, and Bioinformatics [ 0887-3585 ] ; 2012-04.
English descriptors
- Teeft :
- Active form, Algorithm, Available structures, Backbone part, Bagglo, Binding events, Binding site, Biol, Campus scientifique, Chem, Cluster, Cluster analysis, Conformation, Conformation number, Conformational, Conformational frames, Conformational selection, Conformational space, Conformers, Conformers ranges, Criterion function, Data points, Default parameters, Different clusters, Different conformations, Docking, Drug design, Drug discovery, Dynamics, Ensemble docking, General flowchart, Helix, Helix bundle, Holo, Holo structures, Important aspect, Intradomain movements, Kinase, Kinase domain, Kinase flexibility figure, Kinase structures, Large body, Large number, Ligand, Ligand binding, Ligand docking, Molecular docking, Molecular dynamics, Molecular dynamics simulations, Molecular recognition, Nancy universite, Next step, Nm1_md, Nm1_md representative, Nm_md, Nm_md sample, Normal mode, Normal modes, Normal modes calculations, Other hand, Other structures, Other techniques, Preliminary analysis, Principal component analysis, Protein backbone, Protein flexibility, Protein structures, Receptor, Receptor conformations, Receptor flexibility, Representative conformations, Representative conformers, Rmsd, Rmsd comparison, Rmsd maps, Rmsd values, Sampling method, Sampling procedure, Secondary structures, Simulation, Stress function, Structural elements, Test case, Trajectory, Virtual screening, Wiley periodicals, Wordom, Wordom analysis.
Abstract
It is now widely recognized that the flexibility of both partners has to be considered in molecular docking studies. However, the question how to handle the best the huge computational complexity of exploring the protein binding site landscape is still a matter of debate. Here we investigate the flexibility of c‐Met kinase as a test case for comparing several simulation methods. The c‐Met kinase catalytic site is an interesting target for anticancer drug design. In particular, it harbors an unusual plasticity compared with other kinases ATP binding sites. Exploiting this feature may eventually lead to the discovery of new anticancer agents with exquisite specificity. We present in this article an extensive investigation of c‐Met kinase conformational space using large‐scale computational simulations in order to extend the knowledge already gathered from available X‐ray structures. In the process, we compare the relevance of different strategies for modeling and injecting receptor flexibility information into early stage in silico structure‐based drug discovery pipeline. The results presented here are currently being exploited in on‐going virtual screening investigations on c‐Met. Proteins 2012;. © 2011 Wiley Periodicals, Inc.
Url:
DOI: 10.1002/prot.24021
Links to Exploration step
ISTEX:19766D458333DB4C556E8BBFD8230A7427053AE2Le document en format XML
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Box 1033 Blindern, 0315 Oslo, Norway</json:string></affiliations></json:item><json:item><name>David W. Ritchie</name><affiliations><json:string>Nancy Université, LORIA/UMR 7503, Équipe‐projet Orpailleur, Campus Scientifique, BP 239, 54506 Vandœuvre‐lès‐Nancy Cedex, France</json:string></affiliations></json:item><json:item><name>Bernard Maigret</name><affiliations><json:string>Nancy Université, LORIA/UMR 7503, Équipe‐projet Orpailleur, Campus Scientifique, BP 239, 54506 Vandœuvre‐lès‐Nancy Cedex, France</json:string><json:string>E-mail: bernard.maigret@loria.fr</json:string><json:string>Correspondence address: Nancy Université, LORIA/UMR 7503, Équipe‐projet Orpailleur, Campus Scientifique, BP 239, 54506 Vandœuvre‐lès‐Nancy Cedex, France===</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>c‐Met protein–ligand complexes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>protein flexibility</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>conformational sampling</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>conformational preselection</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>induced fit</value></json:item></subject><articleId><json:string>PROT24021</json:string></articleId><arkIstex>ark:/67375/WNG-4CL592TS-4</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>It is now widely recognized that the flexibility of both partners has to be considered in molecular docking studies. However, the question how to handle the best the huge computational complexity of exploring the protein binding site landscape is still a matter of debate. Here we investigate the flexibility of c‐Met kinase as a test case for comparing several simulation methods. The c‐Met kinase catalytic site is an interesting target for anticancer drug design. In particular, it harbors an unusual plasticity compared with other kinases ATP binding sites. Exploiting this feature may eventually lead to the discovery of new anticancer agents with exquisite specificity. We present in this article an extensive investigation of c‐Met kinase conformational space using large‐scale computational simulations in order to extend the knowledge already gathered from available X‐ray structures. In the process, we compare the relevance of different strategies for modeling and injecting receptor flexibility information into early stage in silico structure‐based drug discovery pipeline. The results presented here are currently being exploited in on‐going virtual screening investigations on c‐Met. 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7503</addrLine><addrLine>Équipe‐projet Orpailleur</addrLine><addrLine>Campus Scientifique</addrLine><addrLine>BP 239</addrLine><addrLine>54506 Vandœuvre‐lès‐Nancy Cedex</addrLine><country key="FR">FRANCE</country><country key="FR"></country></address></affiliation><note type="foot">Yasmine Asses and Vishwesh Venkatraman contributed equally to this work.</note></author><author xml:id="author-0001"><persName><forename type="first">Vishwesh</forename><surname>Venkatraman</surname></persName><affiliation><orgName type="institution">Nancy Université</orgName><address><addrLine>LORIA/UMR 7503</addrLine><addrLine>Équipe‐projet Orpailleur</addrLine><addrLine>Campus Scientifique</addrLine><addrLine>BP 239</addrLine><addrLine>54506 Vandœuvre‐lès‐Nancy Cedex</addrLine><country key="FR">FRANCE</country><country key="FR"></country></address></affiliation><note type="foot">Yasmine Asses and Vishwesh Venkatraman contributed equally to this work.</note></author><author 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type="book-DOI">10.1002/(ISSN)1097-0134</idno><idno type="book-part-DOI">10.1002/prot.v80.4</idno><idno type="product">PROT</idno><imprint><biblScope unit="vol">80</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="1227">1227</biblScope><biblScope unit="page" to="1238">1238</biblScope><biblScope unit="page-count">12</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-04"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><head>Abstract</head><p>It is now widely recognized that the flexibility of both partners has to be considered in molecular docking studies. However, the question how to handle the best the huge computational complexity of exploring the protein binding site landscape is still a matter of debate. Here we investigate the flexibility of c‐Met kinase as a test case for comparing several simulation methods. The c‐Met kinase catalytic site is an interesting target for anticancer drug design. In particular, it harbors an unusual plasticity compared with other kinases ATP binding sites. Exploiting this feature may eventually lead to the discovery of new anticancer agents with exquisite specificity. We present in this article an extensive investigation of c‐Met kinase conformational space using large‐scale computational simulations in order to extend the knowledge already gathered from available X‐ray structures. In the process, we compare the relevance of different strategies for modeling and injecting receptor flexibility information into early stage <hi rend="italic">in silico</hi> structure‐based drug discovery pipeline. The results presented here are currently being exploited in on‐going virtual screening investigations on c‐Met. 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type="short" xml:lang="en">Exploring c‐Met Kinase Flexibility</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1" noteRef="#fn1"><personName><givenNames>Yasmine</givenNames><familyName>Asses</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1" noteRef="#fn1"><personName><givenNames>Vishwesh</givenNames><familyName>Venkatraman</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Vincent</givenNames><familyName>Leroux</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>David W.</givenNames><familyName>Ritchie</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1" 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Additional Supporting Information may be found in the online version of this article.
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Proteins 2012;. © 2011 Wiley Periodicals, Inc.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Yasmine Asses and Vishwesh Venkatraman contributed equally to this work.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Exploring c‐Met kinase flexibility by sampling and clustering its conformational space</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Exploring c‐Met Kinase Flexibility</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Exploring c‐Met kinase flexibility by sampling and clustering its conformational space</title></titleInfo><name type="personal"><namePart type="given">Yasmine</namePart><namePart type="family">Asses</namePart><affiliation>Nancy Université, LORIA/UMR 7503, Équipe‐projet Orpailleur, Campus Scientifique, BP 239, 54506 Vandœuvre‐lès‐Nancy Cedex, France</affiliation><description>Yasmine Asses and Vishwesh Venkatraman contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vishwesh</namePart><namePart type="family">Venkatraman</namePart><affiliation>Nancy Université, LORIA/UMR 7503, Équipe‐projet Orpailleur, Campus Scientifique, BP 239, 54506 Vandœuvre‐lès‐Nancy Cedex, France</affiliation><description>Yasmine Asses and Vishwesh Venkatraman contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vincent</namePart><namePart type="family">Leroux</namePart><affiliation>Nancy Université, LORIA/UMR 7503, Équipe‐projet Orpailleur, Campus Scientifique, BP 239, 54506 Vandœuvre‐lès‐Nancy Cedex, France</affiliation><affiliation>University of Oslo, Chemistry Department, P.O. 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However, the question how to handle the best the huge computational complexity of exploring the protein binding site landscape is still a matter of debate. Here we investigate the flexibility of c‐Met kinase as a test case for comparing several simulation methods. The c‐Met kinase catalytic site is an interesting target for anticancer drug design. In particular, it harbors an unusual plasticity compared with other kinases ATP binding sites. Exploiting this feature may eventually lead to the discovery of new anticancer agents with exquisite specificity. We present in this article an extensive investigation of c‐Met kinase conformational space using large‐scale computational simulations in order to extend the knowledge already gathered from available X‐ray structures. In the process, we compare the relevance of different strategies for modeling and injecting receptor flexibility information into early stage in silico structure‐based drug discovery pipeline. The results presented here are currently being exploited in on‐going virtual screening investigations on c‐Met. 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